Backbone-modified nucleic acids

Over the last four decades, synthetic non-enzymatic oligonucleotide ligations have been explored as potential models for the evolution of replicating systems on the early Earth [2-11]. These studies have explored ligation reactions that occur on a template without protein/enzymatic catalysis. Such systems have both provided mechanisms for the early evolution of biopolymer catalysts and placed limits on template directed ligation. More recently, the lure of antisense molecules capable of disrupting specific gene expression has resulted in the exploration of backbone-modified nucleic acids [12-33]. 

Generally PNAs have modified polymer backbones (phosphate groups and sugar moieties) and/or modified nucleic acid bases. These analogues can be classified by their preparation methods ... 

Anyhow, a combination of the Scatchard technique and Raman spectroscopy shows (i) that SOAz actually interacts with DNA at the level of ribose backbones and (ii) that this kind of interaction does not drastically modify the DNA secondary structure, ethidium bromide encountering no more difficulty to intercalate between DNA plates SOAz being grafted or not on the nucleic acid. Thus, the behaviour of MYKO 63 and of SOAz appears quite different with respect to their mode of interaction with DNA despite their close chemical and molecular structure. This surprising observation may be of interest for understanding why SOAz does not induce any cumulative toxicity in vivo in contrast with MYKO 63. 

These applications require the use of FON probes resistant to nucleases. ONs with modified backbones such as oligo-2 -0-methyl-2 -deoxyribonucleotides (19), oligo-a-deoxy ribonucleotides (29), peptide nucleic acids (33) and locked nucleic acids (LNA) (50) (Fig. 4) are often used because of the commercially available building blocks. They form, with the RNA targets, hybrids that are not RNAse H substrates unless they can stimulate degradation of the targets rather than report on their presence. 

Both peptide nucleic acids (PNA) [82,83] and locked nucleic acids (LNA) [84] may increase hybrid stability, and have great potential to meet these conditions, imless non-standard binding produces an intolerably high level of artifacts. Unfortunately, the modified chemical backbone of such probes may limit use of en-... 

Both mechanical means and transfection reagents, among others, have been used to facilitate the cellular uptake of oligonucleotides. The application of intraluminal pressure enhances the uptake of particular oligonucleotides in vascular tissues such as carotid arteries or venous bypass grafts [14, 15]. Other approaches use chemical modifications in order to secondarily modify the nucleic acid backbone [16, 17]. In general, these modifications increase uptake through the cell membrane based on the classical receptor-mediated endocytosis pathway. However, once inside the cell, most nucleic acid compounds taken up by endocytosis are ultimately trapped in the lysosomal compartment... 

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